Rickettsia: Typhus group – R. prowazekii, R. typhi

OVERVIEW: What every practitioner needs to know

Are you sure your patient has typhus? What should you expect to find?

• The clinical manifestations of endemic typhus and epidemic typhus in humans are similar, except that the endemic typhus is generally less severe. They both begin with abrupt fever and other nonspecific symptoms, including severe headaches, myalgias, arthralgias, nausea, and vomiting.

• The rash accompanying these symptoms is seen in 20 to 80% of patients. It is observed 7 days, on average, after the onset of fever. It is detected even less frequently in patients with dark skin. The rash at early stages is often discrete, consisting of pink macular lesions that then become maculopapular. The rash usually starts on the trunk (Figure 1) and then spreads centrifugally. It usually does not spread to the face, palms, or soles.

• Neurologic complications, such as papilledema, hemiparesis, or facial nerve palsy have been observed in some patients.

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Figure 1.

How did the patient develop typhus? What was the primary source from which the infection spread?

• Epidemic typhus is caused by Rickettsia prowazekii, which is transmitted to humans by the infected body louse, Pediculus humanus corporis (Figure 2).

• The transmission of R. prowazekii occurs via contamination of broken skin, conjunctivae, or mucous membranes by the feces or crushed bodies of infected lice. R. prowazekii can persist for 100 days in the feces of lice.

• Infection through aerosols of feces-infected dust has been also reported and constitutes the main risk to the physician of contracting typhus. The lice have a tendency to desert febrile hosts to seek healthy individuals, thus efficiently spreading disease in human populations.

• Persons with latent R. prowazekii infection are the main reservoir allowing bacterial survival and maintenance in nature.

• An extrahuman reservoir of R. prowazekii of American origin, involving flying squirrels and their ectoparasites naturally infected with R. prowazekii, has been reported. Cases of human R. prowazekii infection are reported in individuals who have contact with these rodents.

• Endemic typhus, caused by R. typhiinfection, is a worldwide zoonosis (Figure 3) maintained in rodents, particularly rats (Rattus rattus and Rattus norvegicus). Human transmission occurs via the rat flea Xenopsylla cheopis (the Oriental rat flea) (Figure 4).

• Human beings and other mammals are contaminated either by inoculation of infected flea feces into disrupted skin or the respiratory tract or by direct flea bite. Species of fleas other than X. cheopis, including Leptopsylla segnisand Echidnophga gallinaceum, have been reported to have a role in the transmission of R. typhi, and the cat flea, Ctenocephalides felis, can also acquire R. typhi by feeding on infected hosts.

• Other ectoparasites, such as lice and mites, have been suggested to have a role in the maintenance and transmission of R. typhi.

Figure 2.

Figure 3.

Figure 4.

Which individuals are of greater risk of developing typhus?

• Epidemic typhus and endemic typhus are suspected in any conditions that facilitate the emergence and the infestation of infected lice and fleas (e.g. crowded situations, during wars or natural disasters).

• Individuals at higher risk include those who are older, men, and those of African origin.

Beware: there are other diseases that can mimic typhus:

• Differential diagnosis of epidemic typhus and endemic typhus includes Rocky Mountain spotted fever, meningococcemia, measles, typhoid fever, meningitis, secondary syphilis, leptospirosis, infectious mononucleosis, and rubella.

• In people who are found to have lice, epidemic typhus can be confused with trench fever and relapsing fever.

• Differential diagnosis between epidemic typhus and endemic typhus is based on a four-fold increase of specific antibody titer in the case of epidemic typhus. The two diseases can also be distinguished by western blot combined with cross-adsorption tests.

• Distinction between the primary infection and the recrudescent form of epidemic typhus, Brill–Zinsser disease, is possible. The latter form is sporadic and not transmissible.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

• Immunofluorescence is the routine diagnostic method. Serum from the convalescent phase is required to confirm the initial diagnosis.

• Molecular detection and identification is used also. This technique is rapid, sensitive, specific, and can be applied to a wide spectrum of samples with different origins (e.g. clinical samples, infected animals, or insects).

• Cell culture can be used to isolate Rickettsia spp. from clinical samples or arthropods, but this technique requires specialized staff and laboratories.

• Relevant laboratory abnormalities include anemia, thrombocytopenia, increased erythrocyte sedimentation rate, increased hepatic transaminase activity, and hypoalbuminemia.

Results that confirm the diagnosis

• The differentiation of epidemic typhus from endemic typhus by serology can only be distinguished by western blot assays combined with cross-adsorption tests.

• Distinction between primary infection and the recrudescent form of epidemic typhus, termed Brill–Zinsser disease, is based on the immunoglobulin M measure in primary infection.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has typhus, what therapies should you initiate immediately?

Doxycycline is the treatment of choice.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection what anti-infective should I order?

• Doxycycline administration should be started in any suspected case without waiting for laboratory confirmation.

• The standard recommended treatment is 200mg doxycycline per day.

• Duration of treatment is linked to the clinical manifestations and should continue at least 3 days after the patient becomes afebrile.

• A single oral dose of 200mg of doxycycline has been effective against epidemic typhus.

• In doxycycline-hypersensitive patients or pregnant women, chloramphenicol can be used as an alternative treatment (50–75mg/kg/day).

• Ciprofloxacin did not protect a patient with epidemic typhus from death. It may be used as an alternative treatment for endemic typhus. However, a poor response to this antibiotic was reported in one case.

2. Other key therapeutic modalities

What complications could arise as a consequence of typhus?

What should you tell the family about the patient's prognosis?

• Possible complications include: seconday bacterial infection, myocarditis, peripheral gangrene, or venous thromboembolism.

• Glucose-6-phosphate dehydrogenase deficiency, chronic alcoholism, hepatic and renal insufficiency, central nervous system abnormalities, and pulmonary compromise are risk factors for the development of severe disease and/or a fatal outcome.

• The mortality rate of endemic typhus was estimated to be 4% in the absence of appropriate antibiotics, and 1% if antibiotics are administered. The mortality rate of epidemic typhus can reach up to 30%.

• The prognosis of endemic typhus is usually favorable, but some patients require intensive care.

• The prognosis of the recrudescent form of epidemic typhus is usually good.

What-if scenarios:

How do you contract typhus and how frequent is this disease?

Typhus group rickettsiae are transmitted by insects (lice for R. prowazekii and fleas for R. typhi).

This association might not be completely specific; other arthropods may be implicated in the epidemiology of these rickettsiae.

R. prowazekii is maintained in nature only by horizontal transmission.

R. typhi is acquired and maintained by both horizontal and vertical transmission.

Epidemic typhus is known to be a disease of the colder months.

Endemic typhus occurs more regularly in warm climates, which may be explained by the faster growth rate of R. typhi in fleas at 24°C or 30°C than at 18°C. Furthermore, fleas propagate efficiently in hot, dry environments.

What pathogens are responsible for these diseases?

The typhus group of rickettsiae includes R. prowazekii, the agent of epidemic typhus, and R. typhi, the agent of endemic typhus (murine typhus).

How do these pathogens cause disease?

After infection, typhus group rickettsiae spread directly to the blood stream where they target endothelial cells. Bacteria bind to the membrane of the target cell and phagocytosis is induced.

Bacteria escape rapidly from the phagosoms into the cytosol.

Nutrients are acquired using transmembrane exchange mechanisms (adenosine-5′-triphosphate/adenosine diphosphate translocases). Typhus group rickettsiae multiply within the cytosol until mechanical lysis. The infection of additional cells occurs, inducing generalized vasculitis and vascular dysfunction.

Inflammatory mediators (cytokines, prostaglandins, and products of coagulation) are released and the phenotype of infected cells and the tightness of interendothelial cell junctions are modified, leading to an increase in microvascular permeability.

Passage of plasma, plasma proteins, and immune cells into surrounding tissues and lesions occurs, leading to rash, edema, and hemorrhage.

Immune cells release proteases and oxygen radicals that can contribute to the severity of tissue damage.

Hypovolemia and hypoperfusion are also observed.

These changes in vital organs are responsible for morbidity and mortality.

In the case of epidemic typhus, after clinical cure bacteria are not totally cleared. Decades later, recrudescence (Brill–Zinsser disease) may occur in susceptible hosts.

What other clinical manifestations may help me to diagnose and manage typhus?

Eschars are absent in typhus group rickettsioses.

Dry cough, pneumonia, constipation, and splenomegaly are observed in some cases.

A crouching posture, “sutama,” caused by myalgia of the leg has been reported in epidemic typhus.

Meningitis, signs of meningismus, seizures, stupor, drowsiness, and hallucinations have been reported in the case of epidemic typhus.

What other additional laboratory findings may be ordered?

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How can typhus be prevented?

The best way to prevent the spread of epidemic and endemic typhus is to limit propagation of lice and fleas and to eliminate conditions that facilitate their infestation.

Delousing measures, designed to reduce louse proliferation, include changing and washing clothes and bathing patients.

Insecticides (10% dichlorodiphenyltrichloroethane, 1% permethrin, 1% malathion), used as dust or spray to clothing and bedding, are also effective louse-eradication measures.

Prevention of endemic typhus can be accomplished by controlling vectors (fleas) and reservoirs (rodents).

Insecticide-dusting campaigns have been used to treat runways, burrows, and pet bedding. Destruction of flea eggs by regular vacuuming of carpets and pet-bedding areas is also beneficial.

An important consideration in the control of endemic typhus is the elimination of household rodents.

When the reservoir is a pet, collars containing insecticide are recommended.

No vaccine against epidemic typhus or endemic typhus is currrently available

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Raoult, D, Woodward, T, Dumler, JS. “The history of epidemic typhus”. Infect Dis Clin North Am. vol. 18. 2004. pp. 127-40. (An historical perspective on epidemic typhus including during World War II.)

Bechah, Y, Capo, C, Mege, JL, Raoult, D. “Epidemic typhus”. Lancet Infect Dis. vol. 8. 2008. pp. 417-26. (Comprehensive reviews of the history of epidemic typhus from its epidemiology to its treatment and prophylaxis.)

Cowan, G. “Rickettsial diseases: the typhus group of fevers—a review”. Postgrad Med J. vol. 76. 2000. pp. 269-72.

Wu, JJ, Huang, DB, Pang, KR, Tyring, SK. “Rickettsial infections around the world, part 2: rickettsialpox, the typhus group, and bioterrorism”. J Cutan Med Surg. vol. 9. 2005. pp. 105-15. (Well summarized reviews about the typhus group fevers.)

Raoult, D, Roux, V. “The body louse as a vector of reemerging human diseases”. Clin Infect Dis. vol. 29. 1999. pp. 888-911. (Well written paper about the body louse and the louse-associated diseases.)

Azad, AF, Radulovic, S, Higgins, JA, Noden, BH, Troyer, JM. “Flea-borne rickettsioses: ecologic considerations”. Emerg Infect Dis. vol. 3. 1997. pp. 319-27. (Description of the ecologic changes of the flea-borne rickettsioses emphasizing that the prevention and public health measures must take into account this aspect.)

Walker, DH, Ismail, N. “Emerging and re-emerging rickettsioses: endothelial cell infection and early disease events”. Nat Rev Microbiol. vol. 6. 2008. pp. 375-86. (This review shows that our knowledge of rickettsial disease pathophysiology is in its infancy.)

Walker, DH, Valbuena, GA, Olano, JP. “Pathogenic mechanisms of diseases caused by “. Ann N Y Acad Sci.. vol. 990. 2003. pp. 1-11. (Excellent papers about the interactions between rickettsiae and endothelial cells: they describe the pathogenesis of rickettsioses.)

Botelho-Nevers, E, Raoult, D. “Host, pathogen and treatment-related prognostic factors in rickettsioses”. Eur J Clin Microbiol Infect Dis. vol. 30. 2011. pp. 1139-50. (Comprehensive review of the factors that influence the outcome of rickettsioses in humans.)

Renvoisé, A, Mediannikov, O, Raoult, D. “Old and new tick-borne rickettsioses”. Int Health. vol. 1. 2009. pp. 17-25. (In this review the current approaches used to diagnose rickettsial diseasesas well as the treatment were explained.)

DRG CODES and expected length of stay

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